A core element of schizophrenia is the presence of persistent, debilitating cognitive impairments. The cognitive abilities most affected-working memory, selective attention, and cognitive flexibility-are called executive functions because they organize goal-oriented behaviors across time. They require the coordinated activity of multiple brain regions that have as a common node the prefrontal cortex (PFC). Executive-function deficits are considered to pose the most important barrier to a schizophrenic person's recovery and reintegration into society. Unfortunately, they are poorly treated by current antipsychotics. The development of effective treatments has been slowed by the fact that there is as yet no clear understanding, at the cellular or systems level, of the causal neural bases of this complex disorder. Recent studies suggest that abnormally decreased inhibitory signaling by neurons releasing gamma-aminobutyric acid (GABA), in particular within the PFC, may cause aberrant neural circuit activity, resulting in the impaired cognition associated with schizophrenia. GABA activity is crucial in shaping the excitability and patterned activity of glutamatergic principal neurons; aberrant GABA signaling would thus dysregulate activity of both local neural circuits and brain-wide networks. If this hypothesis is accurate, then drugs that increase GABA tone may restore or improve cognitive function. The overarching goal of the proposed research project is to test the hypothesis that diminished GABAergic signaling is a fundamental factor contributing to schizophrenia-associated cognitive deficits. Two complementary, yet independent, approaches will be used. The first approach will evaluate the cognitive effects of GABA system modulators injected directly into the rat prefrontal cortex. Drugs that act at GABA modulatory sites, including allosteric sites on GABAA receptors, cannabinoid CB1 receptors, and GABA transporters, will be tested for their effects on tasks that measure working memory, recognition memory, and cognitive flexibility, and, in particular, for their abilities to block or attenuate cognitive impairments induced by administering the noncompetitive N-methyl-D-aspartate (NMDA) receptor antagonist MK-801. Low-dose NMDA antagonist administration induces a widely used preclinical model of schizophrenia; it is thought to impair cognition by interfering with GABA function. If schizophrenia-like cognitive impairments are caused by reduced GABA signaling, then drugs that augment GABA signaling should block or attenuate the cognitive deficits. Conversely, drugs that act on GABA signaling to further decrease inhibitory activity should exacerbate the effects of MK- 801. The second approach will identify the neural networks activated by performing tasks that measure executive function and will characterize how network activity is altered by MK-801, alone and in combination with GABA modulators. Network activity will be identified by quantifying regional behavior-dependent changes in levels of the protein products of two immediate early genes, Fos and Arc. Fos expression indicates general behavior-dependent neural activation; Arc expression marks regions of synaptic plasticity and information storage. These experiments will provide useful evidence for or against GABA dysfunction as a causal mechanism of schizophrenia-associated cognitive deficits and will furnish deep understanding of the neural bases of executive cognitive functions in a widely used rat model of schizophrenia. PUBLIC HEALTH RELEVANCE: The cognitive problems associated with schizophrenia, which include impaired memory, attention, and flexibility of thought, are considered to be the major obstacle affecting treatment outcome and quality of life. Unfortunately, cognitive impairments are not adequately treated by current antipsychotic medications. The proposed experiments, by testing the hypothesis that schizophrenia-associated cognitive impairments are due to reduced neural inhibition, and identifying brain regions associated with cognitive functions using a rat model of the disorder, will help determine the causal mechanisms of schizophrenia-associated cognitive impairments and will greatly aid in the development of new treatments.